The natural course of a disease in a human may take years to manifest symptoms; to overcome this problem, tractable aquatic genome models employing organisms that can mimic a disease in shorter time periods with genetic power have been created. Going forward we believe attaining the highest possible genome reference quality that we propose here will have a profound effect on funded aquatic research. In essence high quality genome references are proven to be a necessity to enable research on so many levels of biological investigation including disease etiology, small molecule drug screening and interactions, canonical disease pathway manifestation, and so many others. To date very few genomes can be classified as near finished, defined as only missing small regions that are recalcitrant to known molecular biology methods. Previously we have built reference genomes for new aquatic models for human disease that have been immediately put to use by several labs whose experimental outcomes are dependent on this resource. We believe we have raised the level of interest in comparative biological scientific inquiry that employ these species and others where such resources did not exist before. The goal of this project is to considerably elevate targeted aquatic genome models in reference assembly quality and accompany each with near complete gene models. Most biologists wish to see genome quality sufficient to not hinder within species studies that rely on transcriptome, transgenic, RNA interference, or gene knockout data for hypothesis testing. Responding to community needs we will apply cutting edge sequencing technology, the newest de novo assembly algorithms and innovative optical mapping techniques to provide a grouping of the highest quality genome references to date. Outcomes include new genome references for Xiphophorus maculatus (platyfish), Astynanax mexicanus (blind cavefish), Fundulus heteroclitus (killifish), Xenopus tropicalis (frog), Aplysia californica (sea hare) and Oryzias latipes (medaka). With a defined series of specific aims we are confident the future for next generation sequencing based approaches to the discovery of aquatic traits linked to human disease and expose future scientists to excite their intellectual ambitions. Achieving these aims will advance our concept of evolutionary medicine, understanding the origins and complexity of various human maladies through our shared genetic past.